Project: Research project

Project Details


Rhabdomyolysis occurs in diverse conditions and accounts for a relatively
common and potentially treatable cause for acute renal failure. So
exposed to excessive amounts of heme proteins discharged during
rhabdomyolysis, the kidney exhibits prompt and prominent renal
vasoconstriction, tubular necrosis and cast nephropathy. We have recently
demonstrated that heme proteins, in addition to inflicting injury, also
elicit an adaptive response in the kidney consisting of the induction of
heme oxygenase coupled to ferritin synthesis. We propose that the
nephrotoxicity of heme proteins accrues from injury to multiple cellular
targets inflicted dominantly, by heme released from heme proteins, as the
latter are oxidized by the kidney. The presence of large amounts of heme
within the intracellular compartment, however, also induces heme oxygenase
and stimulates ferritin synthesis, a response that affords the clearance
of heme and the sequestration of iron, the latter released when heme is
degraded. The present proposal analyzes the linkage between injury and
adaptation in the kidney induced by heme proteins in vivo and in vitro.
The application also seeks to define aspects of renal function, in
particular renal oxidative metabolism, that render the kidney vulnerable
to heme-mediated toxicity. Additionally we propose that heme proteins
directly induce renal vasoconstriction by virtue of the long recognized
avidity with which heme proteins bind nitric oxide. Finally, we explore
the extent to which the induction of heme oxygenase and ferritin underlies
the phenomenon of cross resistance to acute renal failure. Our specific
aims include i) the factors regulating the expression of heme oxygenase
and ferritin in vivo in experimental rhabdomyolysis, ii) the mechanisms
influencing the induction of heme oxygenase and ferritin by heme proteins
in the intact kidney in vivo, and the correlation of such induction with
renal injury, iii) the determinants and cellular targets of heme protein
toxicity to renal epithelial cells in vitro and the correlation of such
injury with induction of heme oxygenase and ferritin, iv) the capacity of
heme proteins to bind nitric oxide as a determinant of vasoconstriction
and, v) the role of induction of heme oxygenase and ferritin as a
mechanism underlying cross resistance to other forms of acute renal
failure. This proposal utilizes maneuvers which independently afford
protection in experimental rhabdomyolysis in vivo, and these include the
prior administration of heme proteins and pyruvate. Such strategies may be
relevant to the therapy and prevention of clinical rhabdomyolysis.
Effective start/end date8/1/936/30/19


  • Medicine(all)